Relapse and non-relapse prediction using a sensitive circulating tumor DNA assay during colorectal cancer postoperative surveillance

This study investigated whether a circulating tumor DNA (ctDNA) assay using digital PCR (dPCR) could provide early relapse detection and disease-free corroboration at molecular level during postoperative surveillance of colorectal cancer (CRC). METHODS The ctDNA dynamics of 52 patients with CRC measured by dPCR targeting 87 individual tumor-specific mutations (1-5 per patient) were compared with results for conventional surveillance using serum tumor markers and computed tomography scanning (CTS). The data were collected between March 2016 and June 2018. RESULTS A total of 1,526 prospectively collected plasma samples from 867 timepoints were analyzed. The average number of ctDNA assays per patient was 16.4 and the median follow-up was 1,503 days (range 322-1,951 days). Among patients with Stage II or higher disease who underwent curative resection as their initial surgery (n=47), patients who were ctDNA-positive during the postoperative period (n= 9) showed a higher risk of relapse than those who had sustained ctDNA-negative results (n=38) (hazard ratio 56.3, 95%CI 7.8–407.0, P < 0.0001). Elevated ctDNA levels were observed in nine of 10 clinical-relapse patients (11 of 13 events) with an average lead time from a ctDNA-positive time-point to clinical relapse of 191.9 days (range 0-376 days). Given periodic CTS surveillance with ctDNA, 218 (57.1%) CTSs were presumed to be unnecessary for clinical relapse detection and a ctDNA assay would still provide a lead time of 307 days (range 45–582 days). CONCLUSION Our findings suggest that the ctDNA assay can reduce the frequency of CTS for relapse diagnosis during postoperative surveillance of CRC. UMIN Clinical Trial Registry number, UMIN000045114 ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial UMIN Clinical Trial Registry number, UMIN000045114 ### Funding Statement This work was supported by a Grant-in-Aid for Scientific Research KAKENHI [16K19951, 16K19952, 16H06279, 17K10605, 19K09224, 20K09064, 20K08966, and 21K07223], Keiryokai Collaborative Research Grant [#136 and #145], and Iwate Prefectural Research Grants [H30, R2, and R3] ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Institutional Review Board of Iwate Medical University (IRB #HGH28-15 and #MH2021-073). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript.